Systemic TM4SF5 overexpression in Apc(Min/+) mice promotes hepatic portal hypertension associated with fibrosis

Mutation of the gene for adenomatous polyposis coli (APC), as seen in Apc(Min/+) mice, leads to intestinal adenomas and carcinomas via stabilization of β-catenin. Transmembrane 4 L six family member 5 (TM4SF5) is involved in the development of non-alcoholic fatty liver disease, fibrosis, and cancer. However, the functional linkage between TM4SF5 and APC or β-catenin has not been investigated for pathological outcomes. After interbreeding Apc(Min/+) with TM4SF5-overexpressing transgenic (Tg(TM4SF5)) mice, we explored pathological outcomes in the intestines and livers of the offspring. The intestines of 26-week-old dual-transgenic mice (Apc(Min/+):Tg(TM4SF5)) had intramucosal adenocarcinomas beyond the single-crypt adenomas in Apc(Min/+) mice. Additional TM4SF5 overexpression increased the stabilization of β-catenin via reduced glycogen synthase kinase 3β (GSK3β) phosphorylation on Ser9. Additionally, the livers of the dual-transgenic mice showed distinct sinusoidal dilatation and features of hepatic portal hypertension associated with fibrosis, more than did the relatively normal livers in Apc(Min/+) mice. Interestingly, TM4SF5 overexpression in the liver was positively linked to increased GSK3β phosphorylation (opposite to that seen in the colon), β-catenin level, and extracellular matrix (ECM) protein expression, indicating fibrotic phenotypes. Consistent with these results, 78-week-old Tg(TM4SF5) mice similarly had sinusoidal dilatation, immune cell infiltration, and fibrosis. Altogether, systemic overexpression of TM4SF5 aggravates pathological abnormalities in both the colon and the liver.